Insulin signaling in organs and its integration in mice

2010 Fiscal Year Final Research Report

• Project/Area Number: 18GS0317
• Research Category: Grant-in-Aid for Creative Scientific Research
• Allocation Type: Single-year Grants
• Research Institution: 独立行政法人・国立国際医療研究センター(研究所) (2010); Research Institute, International Medical Center of Japan (2008-2009); Kobe University (2006-2007)
• Principal Investigator: KASUGA Masato 独立行政法人・国立国際医療研究センター(研究所), 研究所, 所長 (50161047)
• Co-Investigator(Kenkyū-buntansha): OGAWA Wataru 神戸大学, 大学院・医学研究科, 准教授 (40294219) ; KIDO Yoshiaki 神戸大学, 大学院・保健学研究科, 准教授 (10335440) ; TAMORI Yoshikazu 神戸大学, 大学院・医学研究科, 戦略的客員教授 (90379397) ; NAKAE Jun 慶應義塾大学, 医学部, 特任教授 (00344573) ; INOUE Hiroshi 金沢大学, フロンティアサイエンス機構, 特任准教授 (50397832) ; MATSUMOTO Michihiro 国立国際医療研究センター, 分子代謝制御研究部, 部長 (90467663) ; 野口 哲也 神戸大学, 大学院・医学研究科, 助手 (10372640)
• Project Period (FY): 2006 – 2010
• Keywords: 糖尿病 / インスリン抵抗性 / 臓器間シグナル伝達

Research Abstract

We revealed organ-specific insulin signaling by generating mice lacking a fundamental molecule for insulin signaling in an organ-specific manner. These mice also revealed signals used to communicate between organs. For example, we found insulin action in the brain inhibited hepatic glucose production via the nervous system. Thus, homeostasis in a whole body is regulated ingeniously by signals used to communicate within organs and between organs.

Research Products

• [Journal Article] CITED2 links hormonal signaling to PGC-lαacetylation in regulation of gluconeogenesis (2012)
  • Author(s): Sakai M., Matsumoto M, Tsujimura T., Cao Y., Noguchi T., Inagaki K., Inoue H., Hosooka T., Takazawa K., Kido Y., Yasuda K., Hiramatsu R., Matsuki Y., Kasuga M
  • Journal Title: Nature Med Volume: (in press)
• [Journal Article] Overexpression of KLF15 in adipocytes of mice results in down-regulation of SCD1 expression in adipocytes and consequent enhancement of glucose-induced insulin secretion (2011)
  • Author(s): Nagare T, Sakaue H, Matsumoto M, Cao Y, Inagaki K, Sakai M, Takashima Y, Nakamura K, Mori T, Okada Y, Matsuki Y, Watanabe E, Ikeda K, Taguchi R, Kamimura N, Ohta S, Hiramatsu R, Kasuga M
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 37458-37469
• [Journal Article] Ablation of TSC2 enhances insulin secretion by increasing the number of mitochondria through activation of mTORC1 (2011)
  • Author(s): Koyanagi M., Asahara S., Matsuda T., Hashimoto N., Shigeyama Y., Shibutani Y., Kannno A., Fuchita M., Mikami T., Hosooka T., Inoue H., Matsumoto M., Koike M., Uchiyama Y., Noda T., Seino S., Kasuga M., Kido Y
  • Journal Title: PLoS ONE
• [Journal Article] Role of S6K1 in regulation of SREBP1c expression in the liver (2011)
  • Author(s): Li S., Ogawa W., Emi A., Hayashi K., Senga Y., Nomura K., Hara K., Yu D., Kasuga M
  • Journal Title: Biochem. Biophys. Res. Commun
• [Journal Article] PDK1-Foxo1 in Agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure (2011)
  • Author(s): Cao Y, Nakata M, Okamoto S, Takano E, Yada T, Minokoshi Y, Hirata Y, Nakajima K, Iskandar K, Hayashi Y, Ogawa W, Barsh G S., Hosoda H, Kangawa K, Itoh H, Noda T, Kasuga M, J Nakae
  • Journal Title: PLoS ONE Volume: 6 Pages: e18324
• [Journal Article] PDK1/FoxO1 pathway in POMC neurons regulates pomc expression and food intake (2010)
  • Author(s): Iskandar K, Cao Y, Hayashi Y, Nakata M, Takano E, Yada T, Zhang C, Ogawa W, Oki M, Chua S Jr, Itoh H, Noda T, Kasuga M, Nakae J
  • Journal Title: Am. J. Physiol. Endocrino. Metab Volume: 298 Pages: E787-798
• [Journal Article] Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action (2010)
  • Author(s): Takashima M, Ogawa W, Hayashi K, Inoue H, Kinoshita S, Okamoto Y, Sakaue H, Wataoka Y, Emi A, Senga Y, Matsuki Y, Watanabe E, Hiramatsu R, Kasuga M
  • Journal Title: Diabetes Volume: 59 Pages: 1608-1615
• [Journal Article] The t-SNAREs syntaxin4 and SNAP23 but not v-SNARE VAMP2 are indispensable to tether GLUT4 vesicles at the plasma membrane in adipocyte (2010)
  • Author(s): Kawaguchi T., Tamori Y., Kanda H., Yoshikawa M., Tateya S., Nishino N., Kasuga M
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 391 Pages: 1336-1341
• [Journal Article] An increase in the circulating concentration of monocyte chemoattractant protein-1 elicits systemic insulin resistance irrespective of adipose tissue inflammation in mice (2010)
  • Author(s): Tateya S, Tamori Y, Kawaguchi T, Kanda H, Kasuga M
  • Journal Title: Endocrinology Volume: 151 Pages: 971-979
• [Journal Article] Ablation of C/EBPυalleviates ER stress and pancreaticυcell failure through induction of GRP78 (2010)
  • Author(s): Matsuda T, Kido Y, Asahara S, Kaisho T, Tanaka T, Hashimoto N, Shigeyama Y, Takeda A, Inoue T, Shibutani Y, Koyanagi M, Hosooka T, Matsumoto M, Inoue H, Uchida T, Koike M, Uchiyama Y, Akira S, Kasuga M
  • Journal Title: J. Clin. Invest Volume: 120 Pages: 115-126
• [Journal Article] PDK1 coordinates survival pathways and beta-adrenergic response in the heart (2009)
  • Author(s): Ito K, Akazawa H, Tamagawa M, Furukawa K, Ogawa W, Yasuda N, Kudo Y, Liao CH, Yamamoto R, Sato T, Molkentin JD, Kasuga M, Noda T, Nakaya H, Komuro I
  • Journal Title: Proc Natl. Acad. Sci. U. S. A Volume: 106 Pages: 8689-8694
• [Journal Article] Muscle-specific overexpression of heparin-binding EGF-like growth factor increases peripheral glucose disposal and insulin sensitivity (2009)
  • Author(s): Fukatsu Y., Noguchi T., Hosooka T., Ogura T., Kotani K., Abe T., Shibakusa T., Inoue K., Sakai M., Tobimatsu K., Inagaki K., Yoshioka T., Matsuo M., Nakae J., Matsuki Y., Hiramatsu R., Kaku K., Okamura H., Fushiki T., and Kasuga M
  • Journal Title: Endocrinology Volume: 150 Pages: 2683-2691
• [Journal Article] The Kruppel-like factor KLF15 inhibits transcription of the adrenomedullin gene in adipocytes (2009)
  • Author(s): Nagare T., Sakaue H., Takashima M., Takahashi K., Gomi H., Matsuki Y., Watanabe E., Hiramatsu R., Ogawa W., Kasuga M
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 379 Pages: 98-103
• [Journal Article] Overexpression of the transcriptional coregulator Cited2 protects against glucocorticoid-induced atrophy of C2C12 myotubes (2009)
  • Author(s): Tobimatsu K., Noguchi T., Hosooka T., Sakai M., Inagaki K., Matsuki Y., Hiramatsu R. and Kasuga M
  • Journal Title: Biochem. Biophys. Res. Commum Volume: 378 Pages: 399-403
• [Journal Article] Fat stress and liver resistance (2008)
  • Author(s): Ogawa W., Kasuga M
  • Journal Title: Science Volume: 322 Pages: 1483-1484
• [Journal Article] FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets (2008)
  • Author(s): Nishino, N., Tamori, Y., Tateya, S., Kawaguchi, T., Shibakusa, T., Mizunoya, W., Inoue, K., Kitazawa, R., Kitazawa, S., Matsuki, Y., Hiramatsu, R., Masubuchi, S., Omachi, A., Kimura, K., Saito, M., Amo, T., Ohta, S., Yamaguchi, T., Osumi, T., Cheng, J., Fujimoto, T., Nakao, H., Nakao, K., Aiba, A., Okamura, H., Fushiki, T., and Kasuga, M
  • Journal Title: J. Clin. Invest Volume: 118 Pages: 2808-2821
• [Journal Article] PDK1 regulates cell proliferation and cell cycle progression through control of cylin D1 and p27Kip1 expression (2008)
  • Author(s): Nakamura K., Sakaue H., Nishizawa A., Matsuki Y., Gomi H., Watanabe E., Hiramatsu R., Tamori-Adachi M., Kitajima S., Noda T., Ogawa W., Kasuga M
  • Journal Title: J. Biol. Chem Volume: 283 Pages: 17702-17711
• [Journal Article] Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice (2008)
  • Author(s): Shigeyama Y., Kobayashi T., Kido Y., Hashimoto N., Asahara S., Matsuda T., Takeda A., Inoue T., Shibutani Y., Koyanagi M., Uchida T., Inoue M., Hino O., Kasuga M., Noda T
  • Journal Title: Mol. Cell Biol Volume: 28 Pages: 2971-2979
• [Journal Article] Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-γphosphorylation (2008)
  • Author(s): Hosooka, T., Noguchi, T., Kotani, K., Nakamura, T., Sakaue, H., Inoue, H., Ogawa, W., Tobimatsu, K., Takazawa, K., Sakai, M., Matsuki, Y., Hiramatsu, R., Yasuda, T., Lazar, MA., Yamanashi, Y., and Kasuga, M
  • Journal Title: Nature Med Volume: 14 Pages: 188-193
• [Journal Article] Skp2 controls adipocyte proliferation during the development of obesity (2007)
  • Author(s): Sakai T., Sakaue, H., Nakamura T., Okada M., Matsuki Y., Watanabe E., Hiramatsu R., Nakayama K., Nakayama K. and Kasuga M
  • Journal Title: J. Biol. Chem Volume: 282 Pages: 2038-2046
• [Journal Article] Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1 (2007)
  • Author(s): Okamoto Y., Ogawa W., Nishizawa A., Inoue H., Teshigawara K., Kinoshita S., Matsuki Y., Watanabe E., Hiramatsu R., Sakaue H., Noda T., Kasuga M
  • Journal Title: Diabetes Volume: 25 Pages: 1000-1009
• [Journal Article] MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity (2006)
  • Author(s): Kanda, H., Tateya, S., Tamori, Y., Kotani, K., Hiasa, K., Kitazawa, R., Kitazawa, S., Miyachi, H., Maeda, S., Egashira, K and Kasuga, M
  • Journal Title: J. Clin. Invest Volume: 116 Pages: 1494-1505
• [Journal Article] Role of hepatic STAT3 in brain insulin action on hepatic glucose production (2006)
  • Author(s): Inoue, H., Ogawa, W., Asakawa, A., Okamoto, Y., Nishizawa, A., Matsumoto, M., Teshigawara, K., Matsuki, Y., Watanabe, E., Hiramatsu, R., Notohara, K., Katayose, K., Okamura, H., Kahn, CR., Noda, T., Takeda, K., Akira, S., Inui, A and Kasuga, M
  • Journal Title: Cell Met Volume: 3 Pages: 267-275
• [Journal Article] Ablation of PDK1 in pancreaticβ-cells induces diabetes as a result of loss ofβ-cell mass (2006)
  • Author(s): Hashimoto, N., Kido, Y., Uchida, T., Asahara, S., Shigeyama, Y., Matsuda, T., Takeda, A., Tsuchihashi, D., Nishizawa, A., Ogawa, W., Fujimoto, Y., Okamura, H., Arden, KC., Herrera, PL., Noda, T and Kasuga, M
  • Journal Title: Nature Genet Volume: 38 Pages: 589-593
• [Journal Article] Insulin resistance and pancreatic s cell failure (2006)
  • Author(s): Kasuga, M
  • Journal Title: J. Clin. Invest Volume: 116 Pages: 1756-1760
• [Presentation] Cited2 regulates hepatic gluconeogenesis by controlling PGC-1αActivity (2010)
  • Author(s): Sakai M., Matsumoto M., Kasuga M
  • Organizer: 11th International Symposium on Insulin Receptor and Insulin Action
  • Place of Presentation: Naples Italy
  • Year and Date: 2010-10-30
• [Presentation] MCP-1 can induce systemic insulin resistance in vivo without inflammation in adipose tissue (2008)
  • Author(s): Tateya S., Tamori Y., Kanda H., Kasuga M
  • Organizer: Keystone Symposia
  • Place of Presentation: Banff, Alberta, Canada
  • Year and Date: 20080219-24
• [Presentation] Muscle-specific overexpression of heparin-binding EGF-like growth factor increases peripheral glucose disposal and insulin sensitivity (2007)
  • Author(s): Fukatsu Y., Noguchi T., Ogura T., Hosooka T., Shibakusa T., Inoue K., Matsuki Y., Hiramatsu T., Kaku K., Fushiki T., Kasuga M
  • Organizer: The 67th Annual Meeting of the American Diabetes Association
  • Place of Presentation: Chicago, IL, U. S. A
  • Year and Date: 20070622-26
• [Presentation] Accumulation of C/EBPυinduces pancreaticυcell failure by reducing the endoplasmic reticulum function (2007)
  • Author(s): Matsuda T, Kido Y, Hashimoto N, Asahara S, Shigeyama Y, Takeda A, Inoue T, Shibutani Y, Uchida T, Kasuga M
  • Organizer: 67^<th> Scientific Session of American Diabetes Association
  • Place of Presentation: Chicago, IL, U. S. A
  • Year and Date: 20070622-26
• [Presentation] Role of TSC2 in the regulation of pancreaticυcell mass (2007)
  • Author(s): Sigeyama Y, Kido Y, Hashimoto N, Asahara S, Matsuda T, Takeda A, Inoue T, Shibutani Y, Uchida T, Noda T, Kasuga M
  • Organizer: 67^<th> Scientific Session of American Diabetes Association
  • Place of Presentation: Chicago, IL, U. S. A
  • Year and Date: 20070622-26
• [Book] 分子糖尿病学の進歩2007 (2007)
  • Author(s): 井上啓,小川渉,春日雅人
  • Total Pages: 28-35
  • Publisher: 金原出版
• [Book] 糖尿病学基礎と臨床 (2007)
  • Author(s): 細岡哲也,野口哲也,春日雅人
  • Total Pages: 116-169
  • Publisher: 西村書店
• [Remarks] Nature Medicineに発表した論(Hosooka, T., et al.雑誌論文)について以下のメディアで報道された(2008年1月21日)
• [Remarks] 読売新聞(大阪)
• [Remarks] 日本経済新聞
• [Remarks] 産経新聞(大阪)
• [Remarks] 神戸新聞
• [Patent(Industrial Property Rights)] 高トリグリセリド血症の予防・治療剤、及びそのスクリーニング法 (2006)
  • Inventor(s): 春日雅人,小川渉,松木泰,渡辺英二郎
  • Industrial Property Rights Holder: 春日雅人,小川渉,松木泰,渡辺英二郎
  • Industrial Property Number: 特許、出願番号2006-279298
  • Filing Date: 2006-10-12
• [Patent(Industrial Property Rights)] 2型糖尿病に対する感受性の判定方法 (2006)
  • Inventor(s): 春日雅人,小川渉,大原毅,廣田勇二,松木泰,渡辺英二郎
  • Industrial Property Rights Holder: 春日雅人,小川渉,大原毅,廣田勇二,松木泰,渡辺英二郎
  • Industrial Property Number: 特許、出願番号2006-106848
  • Filing Date: 2006-04-07
• [Patent(Industrial Property Rights)] 糖・脂質代謝能の改善剤およびそのスクリーニング方法 (2006)
  • Inventor(s): 春日雅人,阪上浩,永禮智基,岡田裕子,松木泰
  • Industrial Property Rights Holder: 春日雅人,阪上浩,永禮智基,岡田裕子,松木泰
  • Industrial Property Number: 特許、出願番号2006-103577
  • Filing Date: 2006-04-04